Without neovascularization and angiogenesis, a tumor will remain dormant and be unable to grow in size beyond a few millimeters. An exceptionally promising approach to improving human cancer treatment involves the discovery and application of new cancer antiangiogenesis drugs. Such approaches to cancer treatment may cause avascular tumors to remain dormant or eventually to undergo necrosis and shrinkage. Further, appropriate combination of antiangiogenesis with cytotoxic drugs should lead to complete elimination of the neoplastic disease.
Applicant has obtained numerous United States patents relating to the compounds of the combretastatin family. These patents are incorporated herein by reference, and are believed to be as listed, most recent first, as follows: 1. U.S. Pat. No. 6,162,930 Anti-mitotic agents which inhibit tubulin polymerization. 2. U.S. Pat. No. 5,569,786 Isolation, structural elucidation and synthesis of novel antineoplastic substances denominated “combretastatin”. 3. U.S. Pat. No. 5,561,122 Combretastatin A-4 prodrug. 4. U.S. Pat. No. 5,529,989 Pancratistatin prodrug. 5. U.S. Pat. No. 5,409,953 Isolation, structural elucidation and synthesis of novel antineoplastic substances denominated “combretastatin”. 6. U.S. Pat. No. 4,996,237 Combretastatin A-4. 7. U.S. Pat. No. 4,940,726 Cell growth inhibitory macrocyclic lactones denominated Combretastatin D-1 and Combretastatin D-2.
Eighteen years ago applicant reported (Pettit et al., 1982) isolation from the South African tree Combretum caffrum (Eckl. Zeyk.) Kuntze the first member of a series of cancer cell growth inhibitory constituents designated the combretastatins. Subsequently, applicant lead the discovery (Pettit and Singh, 1987) of combretastatin A-2 (1a) and more recently applicant has focused on improving the original synthesis of this potent inhibitor of microtubule assembly and mitosis (Lin et al., 1988 and 1989) as well as converting it to a useful phosphate prodrug (2). Those objectives form the basis of this contribution and are considered very important owing to the powerful vascular targeting (Grosior et al., 1999; Tozer et al., 1999) and anticancer properties of the closely related combretastatin A-4 (1b, Pettit et al, 1989) and its sodium phosphate prodrug (Pettit and Rhodes, 1998). The latter has led to promising results in current Phase I human cancer clinical trials (Remick et al., 1999; Rustin et al., 1999).